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@ARTICLE{Hablesreiter:305557,
      author       = {R. Hablesreiter and P. M. Strzelecka and K. Kopp and N.
                      Estrada and A. Dolnik and M. Tilgner and C. Fustero-Torre
                      and F. Thol and F. H. Heidel and M. Heuser and L. Haghverdi
                      and L. Bullinger$^*$ and F. Christen and F. Damm$^*$},
      title        = {{R}esolving intra-tumor heterogeneity and clonal evolution
                      of core-binding factor acute myeloid leukemia patients with
                      single-cell resolution.},
      journal      = {Experimental hematology $\&$ oncology},
      volume       = {14},
      number       = {1},
      issn         = {2162-3619},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2025-02227},
      pages        = {127},
      year         = {2025},
      abstract     = {Reconstructing and understanding intra-tumor heterogeneity,
                      the coexistence of multiple genetically distinct subclones
                      within the tumor of a patient, and tumor development is
                      essential for resolving carcinogenesis and for identifying
                      mechanisms of therapy resistance. While bulk sequencing can
                      provide a broad view on tumoral complexity/heterogeneity of
                      a patient, single-cell analysis remains essential to
                      identify rare subclones that might drive chemotherapy
                      resistance. In this study, we performed an integrated
                      analysis of bulk and single-cell DNA sequencing data of
                      core-binding factor acute myeloid leukemia patients, defined
                      by the presence of a RUNX1::RUNX1T1 or CBFB::MYH11 fusion
                      gene. By single-cell sequencing, we inferred tumor
                      phylogenies for 8 patients at diagnosis including
                      patient-specific somatic variants, somatic copy-number
                      alterations and fusion genes, and studied clonal evolution
                      under the pressure of chemotherapy for 3 patients. As a
                      result, we developed an approach to reliably integrate
                      subclonal somatic copy number alterations into phylogenetic
                      trees and clonal evolution analysis, obtaining unprecedented
                      resolution of intra-tumor heterogeneity in CBF AML. We were
                      able to show that the fusion gene is among the earliest
                      events of leukemogenesis at single-cell level. We identified
                      remaining tumor clones in 6 patients with complete remission
                      samples indicating incomplete eradication of the tumor
                      clones. Here, we show that identifying the order of mutation
                      acquisition can provide valuable insights into evolutionary
                      history, offering a framework to improve drug selection in
                      the era of targeted therapies.},
      subtyp        = {Letter},
      keywords     = {AML (Other) / CBF (Other) / Clonal evolution (Other) /
                      Clonal heterogeneity (Other) / Intra-tumor heterogeneity
                      (Other) / Single-cell DNA sequencing (Other)},
      cin          = {BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41152985},
      doi          = {10.1186/s40164-025-00718-4},
      url          = {https://inrepo02.dkfz.de/record/305557},
}